The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. Therefore, it is necessary to understand the actions of abused drugs such as marijuana, cocaine, and opioids on physiology of this system. In addition, this brain nucleus is known to mediate motivational aspects of behavior. For this reason it has been implicated in a variety of psychiatric disorders that involve alterations in mood and motivation, as well as in the process of drug addiction. The NAc medium spiny GABAergic output neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to the rewarding properties of these drugs. In addition, drugs of abuse are known to increase NAc dopamine (DA). One role of DA in regulating NAc activity may be to contribute to the long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. However, the precise mechanisms through which such synaptic plasticity develops, and how drugs of abuse, including cannabinoids (CBs), alter such synaptic plasticity, remain poorly understood. To investigate the actions of CBs in the NAc, we are utilizing both electrophysiological and voltammetric recording techniques in brain slices. By combining these approaches, we hope to be able to simultaneously monitor changes in DA levels and the development of synaptic plasticity. Accomplishments attributable to this project in the past year include the development of a voltammetric recording system to measure changes in DA levels in near real-time (100 ms resolution). We have begun to perform recordings in both wildtype and CB1-receptor knockout mice, in order to address whether the loss of the CB1 receptor alters DA signaling in the NAc. These studies are ongoing, and additional data are to be presented at the 2008 Winter Conference on Brain Research.[unreadable] A second project involves ongoing studies with Dr. Bruce Hope investigating the effects of repeated cocaine treatment on synaptic inputs to MSNs. To do this, we are using rats that express a fluorescent marker in a discrete population of MSNs as a result of cocaine sensitization. By visualizing these specific neurons in our slice preparation, we can perform electrophysiological recordings from these cells and assess the mechanisms supporting cocaine sensitization.